Activation of inflammatory signaling pathways within the CNS, including increased expression of proinflammatory cytokines, microglial activation, and other tell-tale signs of neuroinflammation, have emerged as powerful drivers of ethanol-dependent behavioral change and neuropathological consequences of ethanol exposure. While ethanol load is certainly a critical determinant of ethanol-induced cytokine changes, virtually nothing is known about how ethanol-induced inflammatory processes are impacted by cues associated with ethanol exposure, or how ethanol-induced inflammatory processes differ across key stages of development, particularly the juvenile-* adolescent> adult continuum, where age of ethanol initiation is most predictive of later Alcohol Use Disorders (AUD). As such, the overarching goal is to identify mechanisms of plasticity in central cytokine responses evoked by ethanol challenge across eariy development in a rodent model. The proposed work will significantly advance our understanding of ethanol-induced (2-4 g/kg) expression bf Interieukin-6 (IL-6), a rapidly induced (3 hr post ethanol) cytokine effect that occurs in key CNS structures relating to learning and memory (hippocampus) and aversive processes (paraventricular nucleus; PVN). Importantly, when ethanol was paired with novel cues (lemon odor in a unique context) across 4 trials, a substantially lower dose of ethanol (0.5-g/kg) on the fifth trial led to a robust increase in IL-6 expression in the hippocampus (but not PVN). This context-dependent sensitization of IL-6 suggests that neuroinfiammatory consequences of ethanol exposure can come under the conditioned control of cues associated with ethanol exposure, thereby providing novel insight into how ethanol-related inflammatory processes transform across the first few ethanol exposures. Three Specific Aims will (1) characterize developmental differences in ethanol-dependent changes in IL-6; (2) identify developmentally critical/sensitive periods for ethanol-induced plasticity; and (3) determine cellular mechanisms of ethanol dependent expression of IL-6. The proposed work will significantly advance our understanding of how ethanol-related inflammatory processes transform as a function of early developmental exposure to alcohol.